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The article presents answers to a quiz regarding cytology, which was published in the previous issue of the journal.

Addresses issues related to cytopathology. Comparison of fine needle aspiration cytology with core needle biopsy in the pre-operative diagnosis of breast lesions; Role of fine needle aspiration biopsy in the management of focal liver lesions.

Background & Aims There is increasing need for accurate assessment of liver fibrosis/cirrhosis. We aimed to develop qFibrosis, a fully-automated assessment method combining quantification of histopathological architectural features, to address unmet needs in core biopsy evaluation of fibrosis in chronic hepatitis B (CHB) patients. Methods qFibrosis was established as a combined index based on 87 parameters of architectural features. Images acquired from 25 Thioacetamide-treated rat samples and 162 CHB core biopsies were used to train and test qFibrosis and to demonstrate its reproducibility. qFibrosis scoring was analyzed employing Metavir and Ishak fibrosis staging as standard references, and collagen proportionate area (CPA) measurement for comparison. Results qFibrosis faithfully and reliably recapitulates Metavir fibrosis scores, as it can identify differences between all stages in both animal samples (p<0.001) and human biopsies (p<0.05). It is robust to sampling size, allowing for discrimination of different stages in samples of different sizes (area under the curve (AUC): 0.93-0.99 for animal samples: 1-16mm2; AUC: 0.84-0.97 for biopsies: 10-44mm in length). qFibrosis can significantly predict staging underestimation in suboptimal biopsies (<15mm) and under- and over-scoring by different pathologists (p<0.001). qFibrosis can also differentiate between Ishak stages 5 and 6 (AUC: 0.73, p=0.008), suggesting the possibility of monitoring intra-stage cirrhosis changes. Best of all, qFibrosis demonstrates superior performance to CPA on all counts. Conclusions qFibrosis can improve fibrosis scoring accuracy and throughput, thus allowing for reproducible and reliable analysis of efficacies of anti-fibrotic therapies in clinical research and practice. [ABSTRACT FROM AUTHOR]

Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a spectrum of pathologies ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. Patients with metabolic associated steatohepatitis (MASH) with and without fibrosis are at greatest risk of liver and cardiovascular complications. To identify such at-risk MASLD patients, physicians are still reliant on invasive liver biopsies. This study aimed to identify circulating lipidomic signatures to better identify patients with MASH in a multi-ethnic Asian cohort., Approach & Results: A lipidomic approach was used to quantify a total of 481 serum lipids from 151 Singaporean patients paired with protocolized liver biopsies. Lipidomic signatures as diagnostic biomarkers for MASLD, MASH and advanced fibrosis were identified. 210 lipids showed significant differences for varying histological subtypes of MASLD. Majority of these lipids were associated with liver steatosis (198/210). We identified a panel of 13 lipids associated with lobular inflammation, ballooning and significant fibrosis. More specifically, dihexosylceramides were novel markers for significant fibrosis. Using the serum lipidome alone, we could stratify patients with MASLD (AUROC 0.863), as well as those with at-risk MASH (AUROC 0.912) and advanced fibrosis (AUROC 0.95). The lipidomic at-risk MASH predictor, using 14 markers, was independently validated (n = 105) with AUROC 0.76., Conclusions: The dynamic shift in blood lipid profile was associated with progressive histological stages of MASLD, providing surrogate markers for distinguishing stages of MASLD as well as identifying novel pathways in the pathogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024. Published by Elsevier Inc.)

We aimed to study the effects of different extensive confluent necrosis on complete biochemical remission, side effects of immunosuppressants, and outcomes in patients with autoimmune hepatitis (AIH). Patients with liver biopsy, receiving standard immunosuppressive therapy (IST), and regular follow-up were retrospectively recruited. Demographic and clinicopathological characteristics between Ishak confluent necrosis scores ≤4 (the non-severe AIH group) and ≥5 (the severe AIH group) were compared. The Kaplan-Meier Survival analysis, Cox regression analysis, and log-rank test were performed. Bilateral p <0.05 was considered statistical significance. One hundred and forty-two patients were enrolled, the median age was 56.0, and 83.8% were female. There were no significant differences in aminotransferases and immunological markers between the two groups. Patients in the severe AIH group had significantly worse liver synthetic function, a higher proportion of cirrhosis, and histologically a higher degree of portal inflammation, interface hepatitis, fibrosis stage, and a higher histological activity index score (all p <0.05). Patients in the severe AIH group had a lower response than the other group after four weeks (57.1% vs. 86.3%, p =0.002). However, differences in complete biochemical remission (CBR) were insignificant. Eight patients experienced end-point events. Kaplan-Meier survival analysis showed no significant difference between the two groups ( p =0.343). For adverse effects of IST, patients in the severe group tended toward a higher incidence of corticosteroid adverse effects without statistical significance. Our study indicated that patients with histologically severe confluent necrosis (Ishak score≥5) had significantly worse liver synthetic function and a higher degree of liver fibrosis before IST. Compared with their counterparts, this subgroup of patients showed delayed biochemical response but eventually comparable CBRs, side effects, and long-term outcomes., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Background: Many clinical trials with potential drug treatment options for non-alcoholic fatty liver disease (NAFLD) are focused on patients with non-alcoholic steatohepatitis (NASH) stages 2 and 3 fibrosis. As the histological features differentiating stage 1 (F1) from stage 2 (F2) NASH fibrosis are subtle, some patients may be wrongly staged by the in-house pathologist and miss the opportunity for enrollment into clinical trials. We hypothesized that our refined artificial intelligence (AI)-based algorithm (qFibrosis) can identify these subtle differences and serve as an assistive tool for in-house pathologists., Methods: Liver tissue from 160 adult patients with biopsy-proven NASH from Singapore General Hospital (SGH) and Peking University People's Hospital (PKUH) were used. A consensus read by two expert hepatopathologists was organized. The refined qFibrosis algorithm incorporated the creation of a periportal region that allowed for the increased detection of periportal fibrosis. Consequently, an additional 28 periportal parameters were added, and 28 pre-existing perisinusoidal parameters had altered definitions., Results: Twenty-eight parameters (20 periportal and 8 perisinusoidal) were significantly different between the F1 and F2 cases that prompted a change of stage after a careful consensus read. The discriminatory ability of these parameters was further demonstrated in a comparison between the true F1 and true F2 cases as 26 out of the 28 parameters showed significant differences. These 26 parameters constitute a novel sub-algorithm that could accurately stratify F1 and F2 cases., Conclusion: The refined qFibrosis algorithm incorporated 26 novel parameters that showed a good discriminatory ability for NASH fibrosis stage 1 and 2 cases, representing an invaluable assistive tool for in-house pathologists when screening patients for NASH clinical trials.

Background and Aims: Nonalcoholic steatohepatitis (NASH) is a common cause of chronic liver disease. Clinical trials use the NASH Clinical Research Network (CRN) system for semiquantitative histological assessment of disease severity. Interobserver variability may hamper histological assessment, and diagnostic consensus is not always achieved. We evaluate a second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) imaging-based tool to provide an automated quantitative assessment of histological features pertinent to NASH., Approach and Results: Images were acquired by SHG/TPEF from 219 nonalcoholic fatty liver disease (NAFLD)/NASH liver biopsy samples from seven centers in Asia and Europe. These were used to develop and validate qFIBS, a computational algorithm that quantifies key histological features of NASH. qFIBS was developed based on in silico analysis of selected signature parameters for four cardinal histopathological features, that is, fibrosis (qFibrosis), inflammation (qInflammation), hepatocyte ballooning (qBallooning), and steatosis (qSteatosis), treating each as a continuous rather than categorical variable. Automated qFIBS analysis outputs showed strong correlation with each respective component of the NASH CRN scoring (P < 0.001; qFibrosis [r = 0.776], qInflammation [r = 0.557], qBallooning [r = 0.533], and qSteatosis [r = 0.802]) and high area under the receiver operating characteristic curve values (qFibrosis [0.870-0.951; 95% confidence interval {CI}, 0.787-1.000; P < 0.001], qInflammation [0.820-0.838; 95% CI, 0.726-0.933; P < 0.001), qBallooning [0.813-0.844; 95% CI, 0.708-0.957; P < 0.001], and qSteatosis [0.939-0.986; 95% CI, 0.867-1.000; P < 0.001]) and was able to distinguish differing grades/stages of histological disease. Performance of qFIBS was best when assessing degree of steatosis and fibrosis, but performed less well when distinguishing severe inflammation and higher ballooning grades., Conclusions: qFIBS is an automated tool that accurately quantifies the critical components of NASH histological assessment. It offers a tool that could potentially aid reproducibility and standardization of liver biopsy assessments required for NASH therapeutic clinical trials., (© 2019 by the American Association for the Study of Liver Diseases.)

The stimulator of interferon genes (STING) in macrophages plays a crucial role in nonalcoholic fatty liver disease (NAFLD) progression. However, there is a lack of evidence from large samples of patients to validate a deleterious role for STING in NAFLD. Moreover, sources of STING-expressing cells that are related to NAFLD remain to be definitively characterized. To investigate STING expression and explore its correlation with NAFLD progression in human subjects, our study involved liver samples from 98 NAFLD subjects and 8 controls. STING and p-TBK1 expression in nonparenchymal liver cells was analyzed and correlated with NAFLD pathological features. Numbers of STING + cells were increased in livers from nonalcoholic steatohepatitis (NASH) patients compared with controls, especially in the liver portal tract of NASH patients with fibrosis (p < 0.05). Moreover, numbers of STING + cells in livers of NASH patients were increased with aggravation of inflammation grade and fibrosis stage (p < 0.05). STING was mainly expressed in macrophages, including monocyte-derived macrophages (CCR2 + , S100A9 + ), Kupffer cells (CD68 + ) and CD163 + macrophages. Compared with controls, numbers of STING + /CCR2 + and STING + /S100A9 + cells were significantly increased in livers from NASH patients with fibrosis and positively correlated with liver inflammation grade and fibrosis stage (p < 0.05). However, numbers of STING + /CD68 + and STING + /CD163 + cells were significantly increased in livers from NASH patients with advanced fibrosis and correlated only with aggravation of fibrosis stage (p < 0.05). Furthermore, compared with controls, NASH patients exhibited significantly increased STING + /p-TBK1 + cell numbers. In a coculture system, the amount of p-TBK1 and the mRNAs of IL1β and IL6 in THP1 macrophages, as well as the amount of α-SMA and the mRNAs of Col1a1, Fn and TGFβ1 in LX2 cells were significantly increased upon STING activation in macrophages (p < 0.05). Therefore, increased STING expression in MoMFs appears to be indicative of NAFLD progression, and STING could be a new target for NAFLD therapy.

We investigated the safety of using umbilical cord-lining stem cells for liver regeneration and tested a novel method for stem cell delivery. Stem cells are known by their ability to repair damaged tissues and have the potential to be used as regenerative therapies. The umbilical cord's outer lining membrane is known to be a promising source of multipotent stem cells and can be cultivated in an epithelial cell growth medium to produce cell populations which possess the properties of both epithelial cells and embryonic stem cells-termed cord-lining epithelial cells (CLEC). Hepatocytes are epithelial cells of the liver and their proliferation upon injury is the main mechanism in restoring the liver. Earlier studies conducted showed CLEC can be differentiated into functioning hepatocyte-like cells (HLC) and can survive in immunologically competent specimens. In this study, we chose a porcine model to investigate CLEC as a treatment modality for liver failure. We selected 16 immune competent Yorkshire-Dutch Landrace pigs, with a mean weight of 40.5 kg, for this study. We performed a 50% hepatectomy to simulate the liver insufficient disease model. After the surgery, four pigs were transplanted with a saline scaffold while seven pigs were transplanted with a HLC scaffold. Five pigs died on the surgical table and were omitted from the study analysis. This study addressed the safety of transplanting human CLEC in a large animal model. The transplant interfaces were evaluated and no signs of cellular rejection were observed in both groups.

Histologically, drug-induced liver injury could be classified into acute hepatitis, chronic hepatitis, acute cholestasis, chronic cholestasis, and cholestatic hepatitis. The correlation between these histologic patterns and long-term clinical outcomes has not been well established. Therefore, we conducted a retrospective cohort study to investigate the association of histologic patterns and long-term clinical outcomes defined as biochemical normalization, persistent abnormal liver biochemistry or death at designated time points. In this study, biochemical classification was determined by R-values; histologic injury pattern was determined by morphological features. Predictive ability of clinical outcomes by these two classifications was assessed using Receiver Operating Characteristic Curves. Logistic regression was performed to identify histologic factors associated with outcomes. Totally, 88 patients with drug-induced liver injury were included for final analysis. Biochemical and histologic classification were consistent in 50 (57%) cases. 53 (60%) cases showed biochemical normalization within 6 months, and a further 11 (13%), 16 (18%), and 6 (7%) cases within 1, 2, and 3 years, respectively. Compared with biochemical classification, histologic injury pattern had better predictive ability for abnormal biochemistry at 6 months (Areas under Receiver Operating Characteristic Curves 0.92 versus 0.60, P < 0.001) and 1 year (Areas under Receiver Operating Characteristic Curves 0.94 versus 0.69, P < 0.001). Interlobular bile duct loss in >25% portal areas was independently associated with abnormal biochemistry at 6 months, 1 year, and 2 years. In conclusion, histologic injury pattern is better correlated with clinical outcome at 6 months and 1 year than biochemical classification. Moderate bile duct loss is an important histologic feature associated with persistent biochemical abnormality at 6 months, 1 year, and 2 years.

Development of cell transplantation for treating liver cirrhosis hinges critically on the availability of animal models for studying human stem cell transplantation. We report an immune-permissive murine model of liver cirrhosis with full clinical correlates of decompensated liver disease, and allows testing efficacy of stem cell transplantation. Liver cirrhosis was induced in Nod-scid gamma(NSG) mice with oral thioacetamide(TA) and compared to controls over 12 months. 4 month TA treated cirrhotic mice were then transplanted intrasplenically with 2million human fetal liver progenitor cells(HFH) and compared with cirrhotic controls 2 months after transplantation. NSG-TA mice developed shrunken and nodular livers with histological evidence of fibrosis as compared to controls. This was associated with evidence of worsening decompensated liver disease, with jaundice, hypoalbuminemia, coagulopathy, and encephalopathy in NSG-TA mice. Transplantation of HFH resulted in improvement in both fibrosis and markers of decompensated liver disease. We have demonstrated that NSG-TA mice can recapitulate the full clinical picture of structural and functional cirrhosis, both of which can be improved by transplantation of human fetal liver cells. This model serves as a valuable tool for validation of in vivo liver stem cell transplantation and opens up opportunities for studying the mechanism how stem cells reverse fibrosis.

Current liver fibrosis scoring by computer-assisted image analytics is not fully automated as it requires manual preprocessing (segmentation and feature extraction) typically based on domain knowledge in liver pathology. Deep learning-based algorithms can potentially classify these images without the need for preprocessing through learning from a large dataset of images. We investigated the performance of classification models built using a deep learning-based algorithm pre-trained using multiple sources of images to score liver fibrosis and compared them against conventional non-deep learning-based algorithms - artificial neural networks (ANN), multinomial logistic regression (MLR), support vector machines (SVM) and random forests (RF). Automated feature classification and fibrosis scoring were achieved by using a transfer learning-based deep learning network, AlexNet-Convolutional Neural Networks (CNN), with balanced area under receiver operating characteristic (AUROC) values of up to 0.85-0.95 versus ANN (AUROC of up to 0.87-1.00), MLR (AUROC of up to 0.73-1.00), SVM (AUROC of up to 0.69-0.99) and RF (AUROC of up to 0.94-0.99). Results indicate that a deep learning-based algorithm with transfer learning enables the construction of a fully automated and accurate prediction model for scoring liver fibrosis stages that is comparable to other conventional non-deep learning-based algorithms that are not fully automated.

In this new era of successful long term suppression of hepatitis B viral replication and consistent eradication of hepatitis C virus the necessity for routine pre-treatment biopsies has often been eliminated. Thus, whether there is utility to perform liver biopsy in chronic viral hepatitis is undergoing re-examination. In response to these changing needs, we have developed a new staging system, the Beijing Classification, for assessment of biopsy specimens from patients with chronic viral hepatitis. The most important novelty of the Beijing Classification is that it includes not only extent (stage) of fibrosis, but the quality of fibrosis, namely if the specimen shows predominantly regressive vs. progressive features (or is indeterminantly balanced between the two), the P-I-R score. This histologic distinction between regressive and progressive fibrosis, while invoked in this particular setting of chronic viral hepatitis, may have applicability to all forms of chronic liver disease. Thus, the review contains a description of the concepts of regression and progression with the aim of empowering pathologists to apply them in histopathologic-clinical correlation research as well as in the specific clinical setting for which it was developed. Also, in light of changing clinical needs, grading of necroinflammatory activity and staging of fibrosis are simplified into three point scales. These simplifications should aid the general diagnostic pathologist in being comfortable and confident in assessing biopsy specimens as the criteria for their distinction are far more precise, with significantly reduced "gray zones" of prior grading/staging systems.

Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as "combined (or mixed) hepatocellular-cholangiocarcinoma." These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, because of a lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This article represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation., Conclusion: It is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin (H&E); immunostains are supportive, but not essential for diagnosis. (Hepatology 2018;68:113-126)., (© 2018 by the American Association for the Study of Liver Diseases.)

Objectives: Investigate subtle fibrosis similarities and differences in adult and pediatric nonalcoholic fatty liver disease (NAFLD) using second harmonic generation (SHG)., Methods: SHG/two-photon excitation fluorescence imaging quantified 100 collagen parameters and determined qFibrosis values by using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) scoring system in 62 adult and 36 pediatric NAFLD liver specimens., Results: Six distinct parameters identified differences among the NASH CRN stages with high accuracy (area under the curve, 0835-0.982 vs 0.885-0.981, adult and pediatric). All portal region parameters showed similar changes across early stages 0, 1C, and 2, in both groups. Parameter values decreased in adults with progression from stage 1A/B to 2 in the central vein region. In children, aggregated collagen parameters decreased, but nearly all distributed collagen parameters increased from stage 1A/B to 2., Conclusions: SHG analysis accurately reproduces NASH CRN staging in NAFLD, as well as reveals differences and similarities between adult and pediatric collagen deposition not captured by currently available quantitative methods., (© American Society for Clinical Pathology, 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Objectives: Comparison of magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI) for differentiating malignant and benign focal liver lesions (FLLs)., Methods: Seventy-nine subjects with 124 FLLs (44 benign and 80 malignant) underwent both MRE and DWI. MRE was performed with a modified gradient-echo sequence and DWI with a free breathing technique (b = 0.500). Apparent diffusion coefficient (ADC) maps and stiffness maps were generated. FLL mean stiffness and ADC values were obtained by placing regions of interest over the FLLs on stiffness and ADC maps. The accuracy of MRE and DWI for differentiation of benign and malignant FLL was compared using receiver operating curve (ROC) analysis., Results: There was a significant negative correlation between stiffness and ADC (r = -0.54, p < 0.0001) of FLLs. Malignant FLLs had significantly higher mean stiffness (7.9kPa vs. 3.1kPa, p < 0.001) and lower mean ADC (129 vs. 200 × 10(-3)mm(2)/s, p < 0.001) than benign FLLs. The sensitivity/specificity/positive predictive value/negative predictive value for differentiating malignant from benign FLLs with MRE (cut-off, >4.54kPa) and DWI (cut-off, <151 × 10(-3)mm(2)/s) were 96.3/95.5/97.5/93.3% (p < 0.001) and 85/81.8/88.3/75% (p < 0.001), respectively. ROC analysis showed significantly higher accuracy for MRE than DWI (0.986 vs. 0.82, p = 0.0016)., Conclusion: MRE is significantly more accurate than DWI for differentiating benign and malignant FLLs., Key Points: • MRE is superior to DWI for differentiating benign and malignant focal liver lesions. • Benign lesions with large fibrous components may have higher stiffness with MRE. • Cholangiocarcinomas tend to have higher stiffness than hepatocellular carcinomas. • Hepatocellular adenomas tend to have lower stiffness than focal nodular hyperplasia. • MRE is superior to conventional MRI in differentiating benign and malignant liver lesions.

Background & Aims: A broad range of hepatocellular nodules has been reported in hepatic vascular disorders. It is not clear whether hepatocellular adenoma (HCA) in this context share the same characteristics as conventional HCA. The aim of this study was to carry out a retrospective multicenter survey of hepatocellular nodules associated with hepatic vascular disorders., Methods: Forty-five cases were reviewed, including 32 Budd-Chiari syndrome (BCS). Benign nodules were subtyped using the HCA immunohistochemical panel., Results: Nodules with a HCA morphology were observed in 11 cases. Six originated in BCS: two were liver fatty acid binding protein (LFABP) negative (one with malignant transformation); two expressed glutamine synthetase (GS) and nuclear b-catenin, two expressed C reactive protein (CRP). Among three cases with portal vein agenesis, one nodule was LFABP negative, two expressed GS and nuclear b-catenin, both with malignant transformation. In a Fallot tetralogy case, there were multiple LFABP negative nodules with borderline features and in a hepatoportal sclerosis case, the nodule looked like an inflammatory HCA. Two additional cases had nodules expressing CRP, without typical characteristics of inflammatory HCA., Conclusion: HCA of different immunohistochemical phenotype can develop in hepatic vascular disorders; they may have a different behavior compared to conventional HCA and be more at risk of malignant transformation., (Copyright © 2015. Published by Elsevier B.V.)

Purpose: To evaluate the effect of intravenous gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA) on estimation of liver stiffness using magnetic resonance elastography (MRE) for detection of liver fibrosis., Materials and Methods: Liver MRI with MRE was performed in 210 subjects on a single 1.5 Tesla clinical MRI scanner. Liver MRE was performed before intravenous Gd-DTPA injection (NC-MRE) and 5 minutes post injection (PC-MRE) using a modified phase-contrast gradient-echo sequence (TR/TE=100/27 ms, FOV = 30-46 cm, 4 x 10 mm slices, gap 5 mm) which automatically generated stiffness maps. Two readers' blinded to clinical details independently performed liver stiffness measurements (LSM) by drawing 2 or more regions of interest (ROI) on the stiffness maps on each of the four slices of NC-MRE and PC-MRE obtained for each patient. The mean LSM in kilopascals (kPa) for NC-MRE and PC-MRE was calculated. The correlation between NC-MRE and PC-MRE LSM was evaluated with a paired t test and Pearson's correlation analysis, and the inter-observer correlation was evaluated using intra class coefficient (ICC) analysis. A receiver operating curve analysis (ROC) was performed to compare accuracies for detection and staging of liver fibrosis in a subgroup of 72 subjects with histological confirmation of liver fibrosis., Results: There was an excellent correlation between NC-MRE and PC-MRE LSM (R(2)=0.98, p<0.001) with no significant differences. The interobserver agreement was also excellent (ICC, 0.94-0.99). There were no significant differences in the cut-off LSM value/accuracy/sensitivity/specificity for detection of significant liver fibrosis with NC-MRE and PC-MRE (2.98 kPa/98.5%/100%/88%, p<0.001 and 3.1 kPa/98.2%/98%/88%, p<0.001 respectively)., Conclusion: Intravenous Gd-DTPA had no significant influence on LSM with MRE and does not significantly affect the diagnostic performance of MRE for fibrosis detection.

Purpose: We evaluated the correlation of MR Elastography (MRE) with morphometric assessment of liver fibrosis in chronic hepatitis B (CHB)., Methods: Thirty-two patients with CHB underwent both MRE and a liver biopsy within a 6-month interval. MRE was performed using standard MRE sequence on a 1.5 Tesla clinical scanner. The liver stiffness (LS) was measured on automatically generated stiffness maps. Morphometric quantification of fibrosis of liver biopsies was performed using a semi-automated image analysis program and expressed as percentage area (Fibro-C-Index). Correlations between MRE, Fibro-C-Index, and histologic fibrosis stages were evaluated. Receiver operating curve (ROC) analysis of MRE and Fibro-C-index for differentiating fibrosis (≥F1), significant fibrosis (≥F2), advanced fibrosis (≥F3), and cirrhosis (F4) was performed., Results: MRE showed excellent correlation with both Fibro-C-Index (r = 0.78, 95% confidence interval [CI], 0.59-0.88, P < 0.001) and histologic staging (rho = 0.87, 95% CI, 0.72-0.94, P < 0.0001). Significant differences in MRE (P = 0.0001) and Fibro-C-Index (P = 0.003) among different stages of liver fibrosis was found. MRE and Fibro-C-Index had similar accuracies for differentiating fibrosis stages: ≥F1 (0.87 versus 0.81, P = 0.6), ≥F2 (0.95 versus 0.94, P = 0.78), ≥F3 (0.98 versus 0.96, P = 0.76), and F4 (1.00 versus 0.92, P = 0.10)., Conclusion: MRE is an excellent noninvasive indicator of liver fibrosis burden in CHB., (Copyright © 2013 Wiley Periodicals, Inc.)

Objectives: We measured the accuracy of magnetic resonance elastography (MRE) for the detection and staging of liver fibrosis in chronic hepatitis B (CHB) and compared it with serum fibrosis markers., Methods: Prospective comparison of MRE and routine serum fibrosis markers, namely serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), ALT/AST ratio (AAR), AST to platelet ratio index (APRI) and prothrombin index (PI), was performed in 63 consecutive CHB patients who underwent MRE and histological confirmation of liver fibrosis within a 6-month interval. Diagnostic performance of MRE and serum markers for staging fibrosis (≥F1), significant fibrosis (≥F2), advanced fibrosis (≥F3) and cirrhosis (F4) was compared., Results: The study group comprised 63 patients (19 female; mean age ± SD, 50 ± 11.9 years). MRE (ρ = 0.94, P < 0.0001), APRI (ρ = 0.42, P = 0.0006), PI (ρ = 0.42, P = 0.0006) and AST (ρ = 0.28, P = 0.028) results correlated significantly with fibrosis stage. MRE was significantly more accurate than serum fibrosis markers for the detection of significant fibrosis (0.99 vs. 0.55-0.73) and cirrhosis (0.98 vs. 0.53-0.77). Sensitivity, specificity, positive predictive and negative predictive values for MRE for significant fibrosis and cirrhosis were 97.4 %, 100 %, 100 % and 96 %, and 100 %, 95.2 %, 91.3 % and 100 %, respectively., Conclusion: MRE is an accurate non-invasive technique for the detection and staging of liver fibrosis in CHB., Key Points: • Magnetic resonance elastography is accurate for liver fibrosis detection and staging. • MR elastography is more accurate than serum tests for staging liver fibrosis. • MR elastography can potentially replace liver biopsy in chronic hepatitis B.

Background: There is no satisfactory treatment for nonalcoholic steatohepatitis (NASH). The Bioenterics intragastric balloon (BIB) can be an effective treatment for weight reduction in obese patients., Objective: We evaluated the efficacy of the BIB in improving the histology of NASH in obese patients., Design: Randomized, controlled study., Setting: University hospital., Patients: Obese patients with body mass indexes (BMI) ≥27 kg/m(2) and who had histologic evidence of NASH were recruited., Intervention: Patients were randomly assigned to a step 1 American Heart Association (AHA) diet plus exercise and BIB placement or step 1 AHA diet plus exercise and sham BIB placement for a period of 6 months., Main Outcome Measurements: Liver histology was the primary outcome measure recorded before and after treatment., Results: A total of 18 patients completed the study. Baseline characteristics of the BIB and sham groups were similar. At 6 months, a significant reduction in the mean BMI was seen in the BIB group (1.52 vs 0.8; P = .0008). The median nonalcoholic fatty liver disease activity scores at the end of treatment were significantly lower in the BIB-treated compared with the sham-treated groups (2 [0.75] vs 4 [2.25]; P = .03). There was a trend toward improvement in the median steatosis scores (1 [0.75] vs 1 [1]; P = .075). There was no change in the median loblular inflammation, hepatocellular ballooning, or fibrosis scores in both groups after treatment., Limitations: Pilot study with small numbers and short duration., Conclusion: Results from this pilot study demonstrated that addition of BIB for 6 months provided a greater loss of BMI and improvement in 2 of 5 histologic parameters of nonalcoholic fatty liver disease. A longer study with larger numbers will be required to prove whether or not the therapy is meaningful in the treatment of NASH., (Copyright © 2012 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.)

Liver biopsy remains the gold standard in monitoring progression of liver fibrosis associated with an abnormal increase in collagen. Descriptive scoring systems are still being widely used to grade biopsy samples. In this study, we propose a new set of features by clustering collagen fibers into three groups first based on their localization and connectivity properties, and then by extracting morphological features of collagen fibers. The new feature set is compared to the earlier features used in classification of liver fibrosis, which were based on the total amount of collagen fibers. Our results show that new features lead to more accurate grading of liver fibrosis.

Purpose: Tumor necrosis factor-alpha (TNF-alpha) is implicated in non-alcoholic steatohepatitis (NASH). Pentoxifylline inhibits TNF-alpha. We wanted to evaluate the efficacy of Pentoxifylline on NASH patients., Methods: Patients with biopsy proven NASH and persistently elevated alanine aminotransferase (ALT) greater than 1.5 times the upper limit of normal were randomized to 3 months of treatment with a step 1 American Heart Association diet and daily exercise with Pentoxifylline or placebo. Liver function tests, serum lipids and TNF-alpha, Interleukin 6 (IL-6), and plasma hyaluronic acid were measured at baseline, at weeks 6 and 12. Categorical data were analyzed by Fisher's exact test while independent sample t-test and Mann-Whitney test were used for continuous data., Results: Eleven patients were randomized into the Pentoxifylline and nine to the placebo group. After 3 months of treatment body mass index (BMI), ALT and aspartate aminotransferase (AST) decreased significantly in both groups. There was no difference between the two groups in reduction of BMI (P = 0.897). There was significantly greater reduction in AST in the Pentoxifylline group (P = 0.038). There was a trend toward lower ALT level (P = 0.065) in the Pentoxifylline group. TNF-alpha and IL-6 decreased significantly in both groups after treatment, but there was no significant difference between the two groups., Conclusion: Three months of Pentoxifylline treatment in combination with diet and exercise results in significantly greater reduction in AST levels in patients with NASH as compared with controls.

This study investigated the effects of probenecid to inhibit the multi-drug resistance-associated protein-1 (MRP-1) in mediating the efflux and myotoxicity in rat skeletal muscles, with administration of rosuvastatin. Male Sprague-Dawley rats were administered daily, for 15 days, with either rosuvastatin (50, 100 or 200 mg/kg) or probenecid (100 mg/kg) alone, or with a combination of rosuvastatin (50, 100 or 200 mg/kg) and probenecid (100 mg/kg). Skeletal muscle toxicity was elevated with probenecid administered with 200 mg/kg/day of rosuvastatin, with the elevation of creatine kinase by 12-fold, alanine aminotrasferase by 10-fold and creatinine by 9-fold at day 15, with no adverse effects observed when probenecid was given alone. Mitochondria ultrastructural damage with enlargement, disruption, cristolysis and vaculation was seen in the soleus and plantaris of animals administered with probenecid and high dosages of statin. These muscles were also expressing more succinic dehydrogenase (SDH)-positive and cytochrome oxidase (CyOX)-positive fibers. Although generally well-tolerated, statins produce a variety of adverse skeletal muscle events. Hydrophilic statins, with reduced levels of non-specific passive diffusion rates into extra-hepatic tissues, are still seen to produce myopathy. This highlights the important roles of transport mechanisms in statin transport at the skeletal muscles. Excessive influx, reduced efflux or the combination of the two could result in elevated cellular levels of statins at the skeletal muscles, resulting in toxicity. This study provides preliminary evidence that the MRP-1 transporter and efflux at skeletal muscles possibly play significant roles in statin-induced myopathy.

The CCAAT/enhancer binding protein alpha (C/EBPalpha) is vital for establishing normal hepatic energy homeostasis and moderating hepatocellular growth. CEBPA loss-of-function mutations identified in acute myeloid leukemia patients support a tumor suppressor role for C/EBPalpha. Recent work showed reductions of C/EBPalpha levels in human hepatocellular carcinoma with the reductions correlating to tumor size and progression. We investigated the potential of reactivating c/ebpalpha expression during hepatic carcinogenesis to prevent tumor cell growth. We have developed a c/ebpalpha knock-in mouse in which a single-copy c/ebpalpha is regulated by one allele of the alpha-fetoprotein (AFP) gene promoter. The knock-in mice are physically indistinguishable from wild-type (WT) controls. However, knock-in animals were found to deposit fetal hepatic glycogen earlier than WT animals. Quantitative real-time PCR confirmed early c/ebpalpha expression and early glycogen synthase gene activation in knock-in fetuses. We then used diethylnitrosamine to induce hepatocellular carcinoma in our animals. Diethylnitrosamine produced half the number of hepatocellular nodules in knock-in mice as in WT mice. Immunohistochemistry showed reduced C/EBPalpha content in WT nodules whereas knock-in nodules stained strongly for C/EBPalpha. The p21 protein was examined because it mediates a C/EBPalpha growth arrest pathway. Nuclear p21 was absent in WT nodules whereas cytoplasmic p21 was abundant; knock-in nodules were positive for nuclear p21. Interestingly, only C/EBPalpha-positive nodules were positive for nuclear p21, suggesting that C/EBPalpha may be required to direct p21 to the cell nucleus to inhibit growth. Our data establish that controlled C/EBPalpha production can inhibit liver tumor growth in vivo.

Background: alpha-Fetoprotein (AFP)-producing carcinomas, hepatoid or otherwise, are increasingly being recognized at extrahepatic sites. Some of them not only mimic hepatocellular carcinomas (HCCs) in having a proclivity for vascular permeation and distant metastases but also exhibit identical morphology and immunoreactivity for alpha-1-antitrypsin and HepPar1. beta-Human chorionic gonadotropin (hCG) is also detected. This would create diagnostic problems in hepatic fine needle aspiration biopsies (FNABs) from patients with elevated serum AFP. Apart from HCC, its variants and germ cell tumors, one must consider metastatic AFP-producing carcinomas., Cases: A man with gastric adenocarcinoma had a liver mass. Hepatic FNAB revealed an AFP-producing adenocarcinoma. The gastric tumor was positive for AFP, polyclonal carcinoembryonic antigen, HepPar1, CK19, hCG and synaptophysin. A woman with endocervical adenocarcinoma had multiple liver nodules. FNAB revealed an AFP-producing, undifferentiated carcinoma. The cervix showed a large cell neuroendocrine carcinoma coexisting with an adenocarcinoma in situ. The large cells were positive for synaptophysin, AFP, hCG and AE1/3. The glands showed diffuse HepPar1 and focal synaptophysin expression., Conclusion: A wide histologic spectrum of extrahepatic carcinomas can produce AFP and other peptide hormones. The true AFP status probably is not recognized at the first presentation. Such carcinomas, whether hepatoid or not, behave aggressively. Their recognition at the initial presentation is crucial to early and appropriate therapy. These entities add a new dimension to the challenges of FNAB diagnosis.